Transforming growth factor (TGF-β) is a family of pleiotrophic cytokines that inhibits the growth of most cell types (including epithelial cells, endothelial cells and lymphocytes). In mammals, the TGF-β family includes TGF-β1, -β2 and -β3. TGF-β is the most potent known stimulator for extracellular matrix synthesis and deposition and plays an important role in wound healing and tissue fibrosis. It has anti-inflammatory and pro-inflammatory activities, depending on the tissue studied.
Among its anti-inflammatory activities, TGF-β suppresses the activity of T cells, B cells, macrophages and NK cells and inhibits the expression of several proinflammatory genes (Piccirillo et al., (1998) J. Immunol. 161, 3950-3956; Prud'homme and Piccirillo, (2000) J. Autoimmun. 14, 23-42; Li, M. et al., (2006) Biochem. Biophys. Res. Commun. 344, 701-707). Because of its growth regulatory, anti-inflammatory and immunomodulatory activities, TGF-β has been identified as a target in the treatment of several diseases. For example, TGF-β somatic gene therapy has been shown to prevent autoimmune disease in nonobese diabetic mice (Piccirillo et al., (1998) J. Immunol. 161: 3950-3956). Injection of TGF-β1 has also been demonstrated to protect mice against collagen-induced arthritis (Kuruvilla et al., (1991) PNAS 88, 2918-2921) relapsing experimental allergic encephalomyelitis (Johns et al., (1991) J. Immunol. 147, 1792-1796), models for rheumatoid arthritis and multiple sclerosis, respectively and allograft rejections (Wallick et al., (1990) J. Exp. Med. 172, 1777-1784). TGF-β has additionally been shown to play a role in atherosclerosis in the cardiovascular system (Grainger D. J. (2004), Arterioscler. Thromb. Vasc. Biol., 24, 399-304; Metcalfe and Grainger (1995), Biochem. Soc. Trans. 23, 403-406). For example, it has been shown that one mechanism by which elevated cholesterol contributes to atherosclerosis is by decreasing the responsiveness of vascular cells to TGF-β (Chen et al., (2007) J. Cell Sci. 120, 3509-3521). TGF-β additionally plays a complex role in carcinogenesis. The cytokine is believed to possess tumor suppressor activity early in carcinogenesis but in later stages, tumor suppressor activity is lost and TGF-β acts as a growth-promoting agent (Derynck et al., (2001) J. Nat. Genet 29, 117-129); Piek and Roberts (2001) Adv. Cancer Res. 83, 1-54; Stover et al., (2007), J. Cell Biochem. 101, 851-861). Other conditions or diseases associated with decreased TGF-beta signaling include Alzheimers disease (Tesseur et al., (2006) J Clin Invest. 116, 3060-3069; Das et al., (2006) J. Clin. Invest. 116: 2855-2857), systemic lupus erythematosus (Ohtsuka et al., (1998) J. Immunol., 160: 2539-2545), chronic wounds (Kim et al., (2003). J. Cell. Phys., 195(3): 331-6), chronic obstructive pulmonary disease (Baraldo et al., (2005) Thorax; 60: 998-1002), inflammatory bowel disease (Fiocchi et al., (2001), J. Clin. Invest. 108(4): 523-526), Guillain-Barre syndrome (Creange et al., (1998), J Neurol Neurosurg Psychiatry 64: 162-165), and Colorectal cancer (Markowitz et al., Science 268, 1336 (1995), Valle et al., (2008) Science: 321, 1361).
Because TGF-β has utility in the treatment of several diseases and conditions, it would be useful to identify agents that enhance TGF-β signaling or increase cells' responsiveness to TGF-β.